Industrial process for preparing tropenol

ABSTRACT

The invention relates to a new industrially useable process for preparing tropenol, optionally in the form of the acid addition salts thereof.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/448,493, filed May 29, 2003, now U.S. Pat. No. 6,747,153 whichapplication claims benefit of U.S. Provisional Application Ser. No.60/407,121, filed on Aug. 30, 2002, and said applications are hereinincorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to a new industrially useable process forpreparing tropenol, optionally in the form of the acid addition saltsthereof.

BACKGROUND TO THE INVENTION

The compound tropenol is known from the prior art and has the followingchemical structure:

The compound may be used as a starting compound for preparingpharmacologically valuable compounds. For example, the compoundstiotropium bromide, ipratropium bromide or also BEA2108 may be mentionedin this context. These pharmacologically valuable substances arecharacterized by the following chemical structures:

Because of the high degree of efficacy of the above compounds they haveto be made available in as pure form as possible using efficient methodsof synthesis. The stringent purity requirements, in particular, withwhich compounds intended for therapeutic use generally have to comply,demand the lowest possible levels of contaminant in the startingcompounds. If materials which contain relatively high levels ofimpurities are used as starting compounds, purification of the endproduct is often difficult as any impurities introduced at the beginningoften cannot easily be removed at later stages of synthesis or only atthe expense of substantial losses of yield. This is particularly thecase when the by-products or impurities present only differ slightlystructurally from the main products in question.

Against this background the problem of the present invention is toprovide a method of synthesis which allows industrial production oftropenol, preferably in the form of one of the acid addition saltsthereof, in a good yield and particularly with a high degree of purity.

DETAILED DESCRIPTION OF THE INVENTION

The problem defined above is solved by the invention describedhereinafter.

The present invention accordingly relates to an industrial process forpreparing tropenol of formula (I)

optionally in the form of the acid addition salts thereof, characterizedin that a compound of formula (II)

wherein

R denotes a group selected from C₁-C₄-alkyl, C₂-C₆-alkenyl andC₁-C₄-alkylene-phenyl, each of which may be substituted by hydroxy orC₁-C₄-alkoxy, optionally in the form of the acid addition salts thereofas well as optionally in the form of the hydrates thereof in a suitablesolvent, is reacted with a formamide-acetal of formula (III)

wherein

R′ denotes C₁-C₄-alkyl and R″ denotes a group selected from C₁-C₄-alkyland C₁-C₄-alkylene-phenyl, to obtain a compound of formula IV

wherein the groups R, R′ and R″ may have the meanings given above, thisis then converted by decarboxylation into an ester of formula (V)

wherein R may have the meanings given above, and lastly this ester issaponified to obtain the compound of formula (I) which is optionallyconverted into an acid addition salt by reaction with a suitable acid.

Preferably, the present invention relates to an industrial process forpreparing tropenol of formula (I), optionally in the form of the acidaddition salts thereof, which is characterized in that a compound offormula (II) wherein R denotes C₁-C₄-alkyl or C₂-C₄-alkenyl is used asstarting material, optionally in the form of the acid addition saltsthereof and optionally in the form of the hydrates thereof, and wherein,in the formamideacetal of formula (III) used, the groups R′ denotemethyl or ethyl and the groups R″ represent methyl, ethyl or propyl.

Most preferably, the present invention relates to an industrial processfor preparing tropenol of formula (I), optionally in the form of theacid addition salts thereof, preferably in the form of itshydrochloride, which is characterized in that a compound of formula (II)wherein R denotes 1-propenyl, 2-propenyl, 1-buten-1-yl, 1-buten-2-yl,1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl or 2-buten-2-yl is used asstarting material, optionally in the form of the acid addition saltsthereof as well as optionally in the form of the hydrates thereof andwherein in the formamide-acetal of formula (III) used the groups R′ andR″ represent methyl or ethyl, preferably methyl.

Most preferably, the compound of formula (II) used is the compoundwherein R denotes 2-buten-2-yl. This compound is also known by the namemeteloidin in the prior art.

The term C₁-C₄-alkyl within the scope of the present invention denotesbranched or unbranched alkyl groups with up to 4 carbon atoms. Examplesinclude methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl and tert-butyl. The term C₁-C₄-alkylene-phenyl within thescope of the present invention denotes phenyl which is linked via abranched or unbranched alkylene bridge having up to 4 carbon atoms.Examples include benzyl, phenyl-2-ethyl, phenyl-1-ethyl,phenyl-3-propyl, phenyl-2-propyl- etc. Both the C₁-C₄-alkyl groups andalso the C₁-C₄-alkylene-phenyl groups may, unless otherwise specified,be substituted by one or more hydroxy and/or C₁-C₄-alkyloxy groups.

By C₂-C₆-alkenyl are meant within the scope of the present inventionbranched or unbranched alkenyl groups with 2 to 6 carbon atoms whichhave at least one double bond. Examples include vinyl, 1-propenyl,2-propenyl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl,2-buten-1-yl, 2-buten-2-yl, butadien-1-yl, butadien-2-yl etc.

Unless otherwise stated, within the scope of the present invention theterm acid addition salts refers to the salts formed with the acidshydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid,tetrafluoroboric acid or hexafluorophosphoric acid, preferablyhydrochloric acid or hydrobromic acid.

According to the invention, the following procedure may be followed forperforming the process for preparing tropenol according to theinvention.

The compound of formula (III) is placed in a suitable reaction vessel.Usually at least 1 mol of the compound (III) is used per mol of thecompound of formula (II) to be reacted. Preferably, between 1.01 and 5.0mol, preferably between 1.1 and 4.0 mol, most preferably between 1.5 and3.0 mol of the compound (III) are put in per mol of the compound (III)to be reacted. Then the compound of formula (II) is added batchwise withstirring. After the addition has ended the mixture obtained is heatedpreferably to a temperature of above 40° C., preferably more than 50°C., most preferably more than 60° C. In the course of the reaction thealcohol R′—OH is released. It is preferably removed from the reactionequilibrium by distillation. This distillation may optionally be carriedout under reduced pressure. If the compound of formula (III) used is thecompound wherein R′ denotes methyl, the temperature is preferablyadjusted to a range from about 55-90° C., more preferably from about60-85° C. After the reaction has ended the compound of formula (III)which was optionally used in excess is removed by distillation underreduced pressure. To do this the mixture obtained is preferably heatedto a temperature of above 40° C., preferably above 50° C., and a vacuumof 100 mbar or less, preferably 60 mbar or less, most preferably 40 mbaror less is applied.

The residue remaining (crude product of general formula (IV)) is thentaken up with stirring in a suitable solvent, preferably in a polarorganic solvent, most preferably in a solvent selected from the groupconsisting of dimethylformamide, acetonitrile, dimethylacetamide andN-methylpyrrolidinone, most preferably dimethylformamide. For example0.001 to 10 L, preferably 0.01 to 5 L, most preferably 0.05 to 1 L ofsolvent may be used per mol of the compound of formula (II) used inorder to prepare this solution.

Preferably at this point about 0.07 to 0.5 L of solvent are used per molof the compound of formula (II) originally put in.

The solution thus obtained is then added, over a period of for example10 minutes to 3 hours, preferably 20 minutes to 2 hours, to stirredacetic anhydride heated to a temperature of more than 70° C., preferablymore than 80° C., preferably more than 90° C., but not more than 139° C.Most preferably, the acetic anhydride used is heated to a temperature ofabout 120-135° C. According to the invention, for example, 1 to 10 mol,preferably 2 to 8 mol, most preferably about 3 to 6 mol of aceticanhydride are used per mol of the compound of formula (II) originallyput in. Preferably, according to the invention, about 4 to 5 mol ofacetic anhydride are used per mol of the compound of formula (II) putin. During this reaction CO₂ is given off. After the addition has endedfor example a further 0.0005 to 5 L, preferably 0.005 to 2,5 L, mostpreferably 0.025 to 0.5 L of the abovementioned solvent are added to thesolution containing the compound of formula (IV) and the resultingmixture is stirred at constant temperature for a further 10 minutes to 6hours, for example, preferably a further 30 minutes to 3 hours, mostpreferably a further 1 to 2 hours. Then all the liquid ingredients ofthe reaction mixture are eliminated by distillation at least 40° C.,preferably at least 50° C., most preferably at about 55-70° C. underreduced pressure, preferably at about 20 mbar or less, preferably atabout 10 mbar or less.

The residue remaining is then taken up in a suitable solvent, preferablyin water and/or a lower alcohol, selected from the group consisting ofmethanol, ethanol and isopropanol, most preferably water, ethanol or amixture thereof. At this point preferably 0.1 to 3 L, most preferablyabout 0.5 to 2 L of one of the abovementioned alcohols mixed with forexample 0.01 to 1 L, preferably 0.05 to 0.5 L of water are used assolvent, per mol of the compound of formula (II) originally put in.

To saponify the ester function of the compound of formula (V) nowpresent in dissolved form this is combined with a suitable base.Suitable bases are preferably inorganic bases, selected from among thealkali or alkaline earth metal carbonates, alkali or alkaline earthmetal alkoxides and alkali or alkaline earth metal hydroxides.Particularly preferred are the hydroxides of lithium, sodium, potassiumand calcium, most preferably sodium or calcium. According to theinvention sodium hydroxide is most preferably used as the base. Theabovementioned bases may be used in pure form or, more preferably, inthe form of aqueous concentrated solutions. If, for example, sodiumhydroxide is used, which is the particularly preferred base, it ispreferably added in the form of aqueous solutions with a concentrationof at least 40 wt. %. It is essential to use at least stoichiometricamounts of base per mol of the compound of formula (II) originally putin. However, it is also possible to use the base in excess. Preferably,about 1.1 to 4 mol, preferably 1.5 to 3 mol, most preferably about 1.7to 2.5 mol of the abovementioned base are used per mol of the compoundof formula (II) originally used. The base may be added to the solutionof the ester of formula (V) for example at a temperature in the rangefrom 0 to 50° C. However, after the base has been added it is preferableto heat the resulting reaction mixture to a temperature above 50° C.,most preferably above 60° C. In a particularly preferred embodiment ofthe present invention, after all the base has been added, the reactionmixture obtained is refluxed with stirring for a period of about 15minutes to 4 hours, preferably 30 minutes to 3 hours, most preferably 1to 2 hours. Then the solvent is eliminated by distillation at least 40°C., preferably at least 50° C., most preferably at about 50-60° C. underreduced pressure, preferably at about 80 mbar or less, preferably atabout 60 mbar or less, most preferably at about 50 mbar or less.

The residue obtained is taken up in water. About 0.01 to 1, preferablyabout 0.1 to 1 L of water are used per mol of the compound of formula(II) originally put in. The tropenol is extracted from this mixture bymeans of a suitable, water-immiscible organic solvent, preferably usinga solvent selected from the group consisting of toluene,methyl-tert-butylether, dichloromethane, chloroform, preferablydichloromethane. According to the invention, a total of between 0.5 and5, preferably between 0.75 and 4 litres of organic solvent are used forthe extraction per mol of the compound of formula (II) used. Theextraction is carried out according to the invention between 3 and 8,preferably 4 to 6 times. After the extraction has ended the organicphases are combined and the organic solvent is distilled off in vacuo.

The crude product remaining is taken up in an organic solvent selectedfrom among methanol, ethanol and isopropanol, preferably isopropanol.According to the invention between 0.1 and 4.0 litres, preferablybetween about 1 and 2 litres of this abovementioned solvent are used permol of the compound of formula (II) originally used. The solutionobtained is optionally filtered. The filtrate contains tropenol offormula (I) in the form of its free base. If the free base is to be usedin the next reaction, the solvent is distilled off in vacuo at thispoint. The remaining free base can then be used in the next steps of thesynthesis, without further purification. According to the invention,however, the free base of tropenol is preferably converted into one ofthe acid addition salts. By the acid addition salts of tropenol aremeant, for the purposes of the present invention, the salts selectedfrom among the hydrochloride, hydrobromide, hydrogen phosphate, hydrogensulphate, tetrafluoroborate or hexafluorophosphate. The hydrobromide andhydrochloride salts are particularly preferred, while tropenolhydrochloride is of particular importance according to the invention. Toprepare the acid addition salts the filtrate is cooled to a temperaturein the range from −20° C. to 20° C., preferably in the range from −10°C. to 15° C. The suspension thus obtained is then combined with thecorresponding acid needed to form the acid addition salts, namely thehydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate,tetrafluoroborate or hexafluorophosphate. At least 1 mol of the acid inquestion should be used per mol of the compound of formula (II)originally used. It may be possible, within the scope of the processesaccording to the invention, to use the acid in excess (i.e. 1.1 to about2-3 mol per mol of the base (II) originally used). According to theinvention the hydrochloride of tropenol is preferably prepared. Thehydrochloric acid required for this may be added either in the form of asolution or in gaseous form. Preferably, hydrogen chloride in gaseousform is added. One of the abovementioned acids is added to the solutionof the free base of the tropenol (I) until a pH of 1 to 5, preferably1.5 to 4, is obtained. After all the acid has been added stirring mayoptionally continue at constant temperature for a further 0.5 to 2hours. Finally, the precipitated acid addition salt of tropenol isseparated off and optionally washed with a solvent selected from amongacetone, methylisobutylketone and methylethylketone, preferably acetone,and dried in vacuo or under an inert gas (such as nitrogen), optionallyat elevated temperature.

As mentioned in the introduction, tropenol, which may be obtained by thepreparation process according to the invention, is a valuable startingcompound for preparing therapeutically active compounds such as forexample tiotropium bromide, ipratropium bromide or BEA2108. Because ofthe high purity in which tropenol can be obtained according to thepresent invention, it is possible to prepare the abovementioned activesubstances in the specifications required for pharmaceutical use.

Accordingly, the present invention further relates to the use oftropenol, optionally in the form of the acid addition salts thereof, asa starting material for preparing therapeutically active compounds suchas for example tiotropium bromide, ipratropium bromide or BEA2108,preferably tiotropium bromide.

The present invention further relates to the use of compounds of formula(II)

wherein R may have the meanings given above, optionally in the form ofthe acid addition salts thereof as well as optionally in the form of thehydrates thereof, as a starting material for preparing therapeuticallyactive compounds such as for example tiotropium bromide, ipratropiumbromide or BEA2108, preferably tiotropium bromide.

Preferably, the present invention relates to the use of meteloidin,optionally in the form of the acid addition salts thereof, as well asoptionally in the form of its hydrates, as a starting material forpreparing therapeutically active compounds such as for exampletiotropium bromide, ipratropium bromide or BEA2108, preferablytiotropium bromide.

The procedure illustrated in Diagram 1 may be used to prepare tiotropiumbromide starting from tropenol.

Starting from the tropenol (I) which may be obtained according to theinvention, first tropenol di-(2-thienyl)-glycolate (VII) is formed byreacting with di-(2-thienyl)-glycolic acid derivatives (VI). This esteris converted by epoxidation of the olefinic double bond into thecorresponding scopine ester (VIII), from which tiotropium bromide can beobtained by reacting with methyl bromide.

Therefore, in a particularly preferred aspect, the present inventionrelates to a process for preparing tiotropium bromide

characterized in that in a first step a compound of formula (II)

wherein R may have the meanings given above, optionally in the form ofthe acid addition salts thereof as well as optionally in the form of thehydrates thereof, is reacted in a suitable solvent with aformamide-acetal of formula (III)

wherein

R′ and R″ may have the abovementioned meanings, to obtain a compound offormula IV

wherein the groups R, R′ and R″ may have the meanings given above, thenthis is converted by decarboxylation into an ester of formula (V)

wherein R may have the meanings given above, and this ester issaponified to obtain tropenol of formula (I), which is reacted,optionally in the form of the acid addition salts thereof, in a secondstep with an ester of formula (VI)

to obtain the tropenol ester of formula (VII)

which is epoxidised in a third step to obtain the scopine ester offormula (VIII)

and this is then quaternised in a fourth step using methylbromide toobtain tiotropium bromide.

The Examples that follow serve to illustrate some methods of synthesiscarried out by way of example in order to prepare tropenol and thetiotropium bromide which may be obtained therefrom. They are intendedsolely as possible procedures, provided as an illustration, withoutrestricting the invention to their content.

EXAMPLE 1 Preparation of Tropenol (I) in the Form of its Hydrochloride

19.5 kg of dimethylformamide dimethylacetal are placed in a suitablysized stirred apparatus and 20.9 kg of meteloidin are added batchwise.After the addition has ended the resulting mixture is slowly heated to atemperature of about 80° C. with stirring. The methanol liberated in thecourse of the reaction is distilled off. After the reaction has endedthe excess dimethylformamide dimethylacetal is distilled off at about50-60° C. under reduced pressure (30 mbar or less). Then 8 Ldimethylformamide are added to the residue remaining and the solutionobtained is cooled to about 45-50° C. with stirring. This solution isthen added, over a period of about 30-70 minutes at about 125-135° C.,to 37.7 kg of stirred acetic anhydride heated to 125° C. Gaseous CO₂ isgiven off. After the addition has ended a further 4 L dimethylformamideare added and the whole reaction mixture is stirred for a further 1.5hours at about 125-135° C. Once the reaction has ended all the liquidconstituents are distilled off by heating to about 60° C. under reducedpressure (about 5 mbar or less). The residue remaining is taken up in 71L ethanol and cooled to about 25° C. with stirring. After the additionof 8 L water and another 10 L ethanol, 45% sodium hydroxide solution(18.3 kg) is added to the resulting mixture. The mixture obtained isrefluxed for about 1.5 hours with stirring. The solvent is thendistilled off at about 50-60° C. under reduced pressure (about 40 mbar)and the residue remaining is taken up in 31 L water. In order to extractthe product 62 L methylene chloride are added. After separation of theorganic phase the aqueous phase remaining is extracted twice more with30 L methylene chloride and 3 times with 21 L methylene chloride. Theorganic phases obtained are combined and the solvent is removed bydistillation. The residue remaining is then taken up in about 35 kg ofisopropanol, combined with 1.6 kg of Clarcel and the resulting mixtureis stirred and filtered. Then at an internal temperature of about −10°C. to +10° C. gaseous hydrogen chloride is piped into the resultingsolution until a pH of about 2-3 is obtained (approx. 3.0 kg of HClgas). Once all the gas has been added the mixture is stirred for anotherhour or so at constant temperature. The solid formed, tropenolhydrochloride, is separated off and dried at about 40-45° C. undernitrogen.

Yield: 11.5 kg of tropenol-hydrochloride (80% based on the meteloidinused)

EXAMPLE 2 Preparation of Tiotropium Bromide

a) Preparation of the Tropenol Ester (VII)

Ammonia (1.8 kg) is piped into 10.9 kg of tropenol hydrochloride(obtainable according to Example 1) in toluene (95 L) at 25° C. Theresulting suspension is stirred for about 1 h at constant temperature.Then the ammonium hydrochloride formed is filtered off and rinsed withtoluene (26 L). At a jacket temperature of about 50° C. some of thetoluene (about 60 L) is distilled off in vacuo. After cooling to about25° C. 15.8 kg of methyl di-(2-thienyl)glycolate are added and theresulting mixture is heated to 50° C. to dissolve it. Toluene (40 L) isplaced in another apparatus and sodium hydride (2.7 kg) is added theretoat about 25° C. The previously formed solution of tropenol and methyldi-(2-thienyl)-glycolate is added to this solution at 30° C. within 1 h.After the addition has ended, the mixture is heated to 75° C. underreduced pressure for about 7 hours with stirring. The methanol formed isdistilled off. The mixture remaining is cooled and added to a mixture ofwater (958 L) and 36% hydrochloric acid (13.2 kg). The aqueous phase isthen separated off and washed with methylene chloride (56 L). After moremethylene chloride has been added (198 L) the mixture thus obtained isadjusted to pH 9 with prepared soda solution (9.6 kg of soda in 45 L ofwater). The methylene chloride phase is separated off and the aqueousphase is stirred with methylene chloride (262 L). The methylene chloridephase is evaporated down to the residue at 65° C. The residue is takenup in toluene (166 L) and heated to 95° C. The toluene solution iscooled to 0° C. The crystals obtained are separated off, washed withtoluene (33 L) and dried at about 50° C. for max. 24 hours in a nitrogencurrent.

Yield: 18.6 kg (83%);melting point: about 160° C. (determined by TLC ata heating rate of 10 K/min);

b) Preparation of the Scopine Ester (VIII)

260 L of DMF are placed in a suitable reaction apparatus and heated to50° C. Then 16.2 kg of tropenol ester (IV) are added and the mixture isstirred until a clear solution is obtained. After cooling to 40° C.,hydrogen peroxide-urea complex (10.2 kg), water (13 L) andvanadium-(V)-oxide (0.7 kg) are added successively batchwise and thecontents of the apparatus are heated to about 50° C. After 2-3 hstirring at constant temperature the mixture is cooled to about 20° C.The reaction mixture obtained is adjusted to about pH 4.0 withhydrochloric acid (36%). Prepared sodium bisulphite solution (2.4 kg in24 L of water) is added. At an internal temperature of 35° C. thesolvent is partially distilled off in vacuo (about 210 L). It is cooledto about 20° C. again and combined with Clarcel (3.2 kg). The pH isadjusted to about 2.0 with dilute hydrochloric acid (36%, 0.8 kg inabout 440 L of water). The resulting solution is filtered and extractedwith methylene chloride (58 L). The methylene chloride phase isdiscarded. Methylene chloride (130 L) is again added to the aqueousphase and the pH is adjusted to about 10.0 with a prepared soda solution(11.0 kg in 51 L of water). The methylene chloride phase is separatedoff and the aqueous phase is extracted with methylene chloride (136 L).Methylene chloride (about 175 L) is distilled off from the combinedmethylene chloride phases in a weak vacuum (600-700 mbar) at 40° C. Thecontents of the apparatus are cooled to 20° C., acetyl chloride (about0.5 kg) is added and the mixture is stirred for about 40 minutes at 20°C. The reaction solution is transferred into a second apparatus. The pHis adjusted to 2.0 with a prepared hydrochloric acid solution (4.7 kg of36% hydrochloric acid in 460 L of water) at 20° C. The methylenechloride phase is separated off and discarded. The aqueous phase iswashed with methylene chloride (39 L). Then methylene chloride (130 L)is added and the pH is adjusted to 10.0 with a prepared soda solution(7.8 kg of soda in 38 L of water) at 20° C. After 15 min. stirring theorganic phase is separated off and the aqueous phase is washed twicewith methylene chloride (97 L and 65 L). The methylene chloride phasesare combined and some of the methylene chloride (90 L) is distilled offin a weak vacuum at a temperature of 30-40° C. Then dimethylformamide(114 kg) is added and the remainder of the methylene chloride isdistilled off in vacuo at 40° C. The contents of the apparatus arecooled to 20° C.

c) Preparation of the Tiotropium Bromide

Methyl bromide (5.1 kg) is piped into the scopine ester solutionobtained by the method described above at 20° C. The contents of theapparatus are stirred at 30° C. for about 2.5 days. 70 L of DMF aredistilled off at 50° C. in vacuo. The solution is transferred into asmaller apparatus. It is rinsed with DMF (10 L). Additional DMF isdistilled off at 50° C. in vacuo until a total amount of distillate ofabout 100 L is obtained. This is cooled to 15° C. and stirred for 2hours at this temperature. The product is isolated using a suctionfilter drier, washed with 15° C. cold DMF (10 L) and 15° C. cold acetone(25 L). It is dried at max. 50° C. for max. 36 hours in a nitrogencurrent. Yield: 13.2 kg (88%);

Melting point: 200-230° C. (depending on the purity of the startingproduct);

The crude product thus obtained (10.3 kg) is added to methanol (66 L).The mixture is refluxed to dissolve it. The solution is cooled to 7° C.and stirred for 1.5 h at this temperature. The product is isolated usinga suction filter drier, washed with 7° C. cold methanol (11 L) and driedfor max. 36 h at about 50° C. in a nitrogen current.

Yield: 9.9 kg (96%); Melting point: 228° C. (determined by TLC at aheating rate of 10 K/min).

If desired, the product thus obtained may be converted in thecrystalline monohydrate of tiotropium bromide. The following method maybe used.

15.0 kg of tiotropium bromide are added to 25.7 kg of water in asuitable reaction vessel. The mixture is heated to 80-90° C. and stirredat constant temperature until a clear solution is formed. Activatedcharcoal (0.8 kg), moistened with water, is suspended in 4.4 kg ofwater, this mixture is added to the solution containing tiotropiumbromide and rinsed with 4.3 kg of water. The mixture thus obtained isstirred for at least 15 min. at 80-90° C. and then filtered through aheated filter into an apparatus which has been preheated to an outertemperature of 70° C. The filter is rinsed with 8.6 kg of water. Thecontents of the apparatus are cooled to a temperature of 20-25° C. at arate of 3-5° C. every 20 minutes. Using cold water the apparatus iscooled further to 10-15° C. and crystallisation is completed by stirringfor at least another hour. The crystals are isolated using a suctionfilter drier, the crystal slurry isolated is washed with 9 L of coldwater (10-15° C.) and cold acetone (10-15° C.). The crystals obtainedare dried at 25° C. for 2 hours in a nitrogen current.

Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).Melting point: 230° C. (determined by TLC at a heating rate of 10K/min).

1. A compound of formula IV

wherein R denotes a group selected from C₁-C₄-alkyl, C₂-C₆-alkenyl andC₁-C₄-alkylene-phenyl, each of which is optionally substituted byhydroxy or C₁-C₄-alkoxy, optionally in the form of the acid additionsalts thereof or the hydrates thereof.
 2. The compound according toclaim 1 wherein R is selected from the group consisting of 1-propenyl,2-propenyl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl,2-buten-1-yl and 2-buten-2-yl.
 3. The compound according to claim 2wherein R is 2-buten-2-yl.
 4. The compound according to claim 1 whereinR is 2-buten-2-yl and R₂ is methyl.